Hydrogen sulfide (H2S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H2S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)-triggered H2S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H2S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H2S until triggered by ROS, such as hydrogen peroxide (H2O2), superoxide (O2−), and peroxynitrite (ONOO−). We demonstrate ROS-triggered H2S donation in live cells and also demonstrate that PeroxyTCM-1 provides protection against H2O2-induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H2S-related therapies.